Discipline(s) enseignée(s)

Biology and biochemistry of cell death

Thèmes de recherche

Epithelial tumor cells have an inherent plasticity that allows their adaptation to stressful conditions induced by the tumor microenvironment, oncogene signaling per se, conventional or targeted therapies. Such adaptation contributes to tumor progression and therapeutic failure by: i) favoring resistance to the deleterious effects of stress; ii) reducing stress in return; iii) initiating programs of self-renewal and of phenotypic transitions that lead to tumor relapse and escape. They might also constitute a vulnerability in themselves when their maintenance is required for tumor progression and dissemination. Because tumor stress phenotypes are highly variable, the success of stress targeting strategies relies on our ability to identify core signaling modules that are at the convergence of many stress sensing pathways, and that are pharmacologically tractable.
BCL-2 family proteins fall in that category. The canonical protective activity anti-apoptotic members exert under these conditions relies in great part on one critical binding interface that can be targeted thanks to the identification and clinical development of small-molecules BH3 mimetics. Our team has worked, during the last years, to show that cancer cells (from the breast in particular) occasionally display a phenotype of « BCL-2 dependency ». We have described some of the structural motifs on which this phenotype relies and showed that not all motifs are equally targeted by BH3 mimetics. We have defined mechanisms that link this phenotype to the Rb and p53 tumor pathways, anti-mitotic therapy, some cell autonomous oncogenic signaling pathways and tumor contexts. We have also provided evidence that BCL-2/BCL-xL are valid targets in human breast cancers. To achieve this, we have developed an organotypic ex vivo culture of breast cancer specimen and wired it to a clinical protocol set in the Nantes Angers Cancer Center (THEREX protocole with ICO).
Based on these results and expertise, we intend to, for the next 5 years:
- describe at a whole cell level how BCL-2 proteins build a dynamic network of mutually exclusive protein-protein interactions of differing robustness to promote stress adaptation
- understand whether and how cancer cells adapt, using comprehensive paradigms that take into acount ECM and cancer associated fibroblasts (CAFs) influences
-investigate whether reliance of BCL-2 proteins evolves during dynamic clonal evolution of breast cancers, and whether, conversely, BCL-2 proteins influences such evolution.
The goal of these studies is to identify pathways that promote stress adaptation in breast cancers, contributing to tumor progression and resistance to conventional and targeted therapies. They will lead to the characterization of markers of therapeutic response, and identify novel targets for innovating treatments.

Dr Philippe Juin obtained his PhD degree in 1995 for his work on mitochondrial assembly. During his post-doc in the UK, he defined the mitochondrial apoptotic pathway as one major intrinsic tumor suppressor mechanism triggered by oncogene deregulation. As a researcher at INSERM, he led increasingly ambitious investigations of the regulation of the mitochondrial apoptotic pathway by Bcl-2 family members in human cancer cells, and of the global impact of this family of proteins on tumor progression. This contributed to establish BCL-2 members as therapeutic targets in solid tumors. In 2012, he became head of an INSERM team who specifically (albeit non exclusively) studies stress adaptation and tumor escape in breast cancers. He has, during the last years, obtained numerous academic and private grants. He is also actively involved in the translational research on breast cancer performed at the Nantes Angers Cancer Center (ICO) . His research contributes to "precision medicine" and should benefit to patients in the medium term: he and other members of the lab have, in particular, created the OTX company, conceived as a tool to develop, and render accessible to numerous care centers, some of the expertise acquired regarding breast cancer tissues.